The long-term goal of my research is to understand how G protein-regulated enzymes and ion channels shape cellular and behavioral responses to drugs of abuse. Toward this end, we are currently studying the cellular and behavioral effects elicited by opiates. Opiates are the most common analgesics administered in the clinic. Unfortunately, opiates with strong analgesic potential such as morphine are also highly addictive. Recent research indicates that the analgesic and addictive effects of morphine are mediated by the G protein-coupled, mu opioid receptor (MOR). Activation of MOR has been linked to the modulation of several downstream enzymes and ion channels, including adenylyl cyclase, voltage-gated calcium channels, and G protein-gated potassium (KG) channels. Relatively little is known, however, regarding the significance of individual enzymes and ion channels to the complex cellular and behavioral effects of morphine. A clearer understanding of the individual contributions of each effector could lead to the development of more selective pain management strategies or treatments for addiction. The primary goal of this component is to determine whether G protein-gated potassium (KG) channel function contributes significantly to the analgesic, locomotor-stimulatory, and reinforcing effects of morphine in mice. In the absence of specific agonists or antagonists for KG channels, we have assembled a large panel of knockout mouse lines lacking one or more of the four KG channel subunits (GIRK1, GIRK2, GIRK3, GIRK4). We will examine the performance of these mice, together with suitable wild-type controls, in hot-plate, locomotor activity, and intravenous self-administration behavioral paradigms. These behavioral studies will demonstrate whether KG channels are critical downstream elements in morphine-induced signaling pathways, and complement other research ongoing in the laboratory aimed at determining KG subunit expression patterns and KG channel coupling to various neurotransmitter signaling systems at the cellular level.